Program Description/Abstract This application is the competitive renewal of my first R01 grant entitled 'The MKP-1/p38 axis: coordinating innate and adaptive immunity'. T cell-mediated immune dysregulation is an important cause of many human inflammatory disorders. For instance, the TH17 subset of effector T cells is highly pathogenic in autoimmune diseases including multiple sclerosis (MS) and its murine model experimental autoimmune encephalomyelitis (EAE). Much emphasis has been placed on T cell-intrinsic molecular and transcriptional pathways in immune reactions, but how T cells interact with innate immunity and target tissues remains elusive. Indeed, the crosstalk between innate and adaptive immunity is a fundamental question in immunology, originally dubbed as 'immunologist's dirty little secret' by the late Dr. Charles Janeway. The identification of TLRs an other pattern-recognition receptors (PRRs) has revolutionized our understanding of immune priming, but it remains unclear how the diverse signals are integrated by intracellular signaling i innate and inflammatory cells to crosstalk with T cells. The central theme of the original grant was to test whether innate immune signals mediated by the MKP-1 and p38 pathway coordinate innate and adaptive immunity. The hypothesis was proven, and we have established p38? as one of the first major signaling pathways in dendritic cells (DCs) to integrate innate and inflammatory signals for programming TH17 differentiation. The potent and unique function of DC p38? signaling in modulating TH17 but not TH1 or TH2 responses presents a remarkable opportunity for mechanistic dissection and therapeutic intervention. Our preliminary results also revealed a role of p38? signaling in TH17 target cells (i.e. CNS-resident cells) in EAE, as well a in DC-mediated inflammatory responses. We hypothesize that the p38?/MKP-1 signaling axis acts in tissue-resident cells and DCs to mediate the crosstalk with T cells and regulate inflammatory responses. To this end, we propose three highly integrated aims, to determine how T cells especially TH17 cells function in EAE by impinging upon tissue-resident cells (Aim 1), to explore how T cell responses are shaped by DC signals (Aim 2), and to further extend this to the reciprocal interaction between T cells and DCs (Aim 3). Thus, the proposal centers upon the p38?/MKP-1 signaling in the non-T cell compartment and its interaction with T cells in biology and disease. Insights gained from this application may significantly impact our understanding of the interface between innate and adaptive immunity and manifest legitimate therapeutic opportunities.